Development of a syn‐Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines

Abstract

Direct coupling of enolizable aldehydes with C-alkynyl imines is realized affording the corresponding propargylic Mannich adducts of syn configuration, thus complementing previous methods that gave access to the anti-isomers. The combination of proline and a urea Brønsted base cocatalyst is key for the reactions to proceed under very mild conditions (3-10 mol % catalyst loading, dichloromethane as solvent, -20 °C, 1.2 molar equivalents of aldehyde) and with virtually total stereocontrol (syn/anti ratio up to 99:1; ee up to 99 %). Some possibilities of further chemical elaboration of adducts are also briefly illustrated.

Enantiodivergence by minimal modification of an acyclic chiral secondary aminocatalyst

“…MeCN as the solvent (The absolute and relative configuration of 5k was determined by comparison with the reported ref. 50 . )…”

“…The resulting products, chiral propargylamines 36 bearing quaternary stereocenters 37–39 , are of synthetic and biological importance 40–46 . Although the catalytic asymmetric direct Mannich reactions of aldehydes with C-alkynyl aldimines have recently emerged 47–50 , the corresponding catalytic asymmetric direct Mannich reactions of aldehydes with C-alkynyl ketimines providing quaternary propargylamines have not yet been realized.…”

Prolinate Salt as a Catalyst in the syn-Selective, Asymmetric Mannich Reaction of Alkynyl Imine

“…Recently Oiarbide, Palomo, and co-workers reported such a reaction for the first time, using proline and urea derivatives as dual catalysts, in which several hydrogen-bonding interactions were proposed. 14 We happened to find that metal or ammonium prolinate is more reactive and selective than the parent proline in the Mannich reaction, which will be described in this communication.…”

N,N‐Diacylaminals as Emerging Tools in Synthesis: From Peptidomimetics to Asymmetric Catalysis

“…[53] Ah ighly suggestive application of the aminal-urea pair has been disclosedi nt he development of as econdary amine-catalyzed syn-selective Mannich reactiono fa ldehydes with propargylic amines (Scheme 19). [54] The combined use of prolinea nd as imple achiral aminal-urea-based cocatalyst provided milder reactionc onditions and higher syn/anti ratios than by using only proline as ac atalyst.Atentative modifiedL ist-Houk-type reactionm odel,i nw hich the tertiary amine-aminal-urea cocatalysth elps the reactants to preorganize, wasp roposed to explain the beneficial effect of dual catalysis.…”